This Program Project focuses on the signaling mechanisms that control the directed outgrowth of neuronal processes and the directed migration of neuronal cells. Together these two properties are essential to neuronal function, since the precise location of neurons and proper interconnection of their axons and their dendrites underpins all neuronal signaling and plasticity Abnormal patterns of neuronal migration have been implicated in human neurological disorders associated with mental retardation, epilepsy, and dyslexia, and congenital disorders of mental retardation are increasingly recognized as having major disorders of axonal and dendritic connections. Moreover, cell surface signaling and cytoskeletal regulation are implicated in degenerative disease such as Alzheimer's disease. Finally, proper axon guidance and axon outgrowth are essential to any possibility of neuronal repair following CNS injury. Until recently it has been controversial whether axon outgrowth and neuronal migration utilized a similar set of signals or whether they used fundamentally different mechanisms. However, several genes including filamin and disabled have recently been shown to be essential to proper neuronal migration to the cerebral cortex, as well as for normal axon outgrowth. This proposal contains three projects that examine 1] molecular regulation of neuronal migration to the cortex, 2] molecular control of axon outgrowth in flies, and 3] molecular control of axon outgrowth via ephrins and Eph receptors. The three linked proposals produce synergy by a] exploiting complementary strengths of mammalian and invertebrate genetic systems, in some cases by studying the same molecular and processes in different organisms, and b] utilizing a core to provide modern imaging technology that is essential for all the diverse projects regardless of the organism of study.